Rapid diffusion of large polymeric nanoparticles in the mammalian brain

Abstract

Non-adhesive particles as large as 110 nm can diffuse rapidly in the brain ECS, if coated with hydrophilic coatings such as PEG coatings and preferably having neutral surface charge. The ability to achieve brain penetration with larger particles will significantly improve drug and gene delivery within the CNS since larger particles offer higher drug payload, improved drug loading efficiency, and significantly longer drug release durations.

We claim: 
     
       1. A dosage formulation for delivery of a therapeutic, prophylactic or diagnostic agent to the brain, the formulation consisting of
 a. polymeric nanoparticles having a diameter of at least about 40 nm and less than about 200 nm, the nanoparticles having a hydrophobic polymeric core and being coated with a hydrophilic polymer comprising polyalkylene oxide or a block copolymer containing polyalkylene oxide blocks, in an amount effective to result in a neutral or near neutral charged surface between −10 mV and 10 mV measured as zeta-potential in phosphate buffered solution, pH 7.0 using laser Doppler anemometry and having a number density of at least 0.1 hydrophilic polymer per nm 2  of nanoparticle surface, wherein the hydrophilic polymer is present in a weight percent of greater than 80% relative to the total weight of the polymeric nanoparticles, 
 b. an effective amount of a therapeutic, prophylactic or diagnostic agent to prevent or treat a disease or disorder of the brain, encapsulated in or on the nanoparticles, and 
 c. a pharmaceutically acceptable excipient for delivery into the brain, 
 wherein the nanoparticles have a diffusion rate at most about 60-fold slower in the brain than in water, whereas the same nanoparticles without the hydrophilic polymer coating have a diffusion rate at least about 16,000-fold slower in the brain than in water, characterized by measuring average effective diffusivities at a time scale of 1 second of respective nanoparticles in cortical tissue relative to in water (D w /D b ). 
 
     
     
       2. The formulation of  claim 1  wherein the nanoparticles are coated with polyethylene glycol or a block copolymer containing polyethylene glycol blocks. 
     
     
       3. The formulation of  claim 1 , wherein the hydrophilic polymer has a number density of at least 0.2, 0.5, 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 90, or 100 hydrophilic polymer per nm 2  of nanoparticle surface. 
     
     
       4. The formulation of  claim 1 , wherein the hydrophilic polymer has a mass of at least 9/10 of the mass of the nanoparticles. 
     
     
       5. The formulation of  claim 1 , wherein the hydrophilic polymer has a weight percent of at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, or greater relative to the total weight of the polymeric nanoparticles. 
     
     
       6. The formulation of  claim 1 , wherein the nanoparticles are formulated for direct injection into the brain. 
     
     
       7. The formulation of  claim 1 , wherein the polymeric core is formed of a biocompatible biodegradable polymer. 
     
     
       8. The formulation of  claim 1 , wherein the nanoparticles have an average diameter of about 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, or 190 nm. 
     
     
       9. The formulation of  claim 1 , wherein the therapeutic, prophylactic or diagnostic agent is loaded at a weight percent of between about 1% and about 80%, between about 1% and about 50%, between about 1% and about 40%, between about 1% and about 20%, or between about 1% and about 10%, relative to the total weight of the nanoparticles and the therapeutic, prophylactic or diagnostic agent. 
     
     
       10. The formulation of  claim 1  in the form of a nanoparticle suspension in an aqueous medium, wherein, following administration, the nanoparticles release an effective amount of the therapeutic, prophylactic or diagnostic agent in the brain over a period of at least 10 minutes, 20 minutes, 30 minutes, one hour, two hours, four hours, six hours, ten hours, one day, three days, seven days, ten days, two weeks, one month, or longer. 
     
     
       11. A method for treating a disease or disorder of the brain, the method comprising administering to the brain the formulation of  claim 1 . 
     
     
       12. The method of  claim 11 , wherein the formulation is administered directly to the brain. 
     
     
       13. The method of  claim 11 , wherein the formulation is administered systemically and the nanoparticles penetrate the brain by passing through the blood-brain barrier. 
     
     
       14. The method of  claim 13 , wherein the formulation is administered in combination with one or more techniques to facilitate passage of the nanoparticles through the blood brain barrier. 
     
     
       15. The method of  claim 14 , wherein the technique is selected from the group consisting of electron paramagnetic resonance, ultrasound, and ultrasound plus microbubbles. 
     
     
       16. The method of  claim 11 , wherein the disease or disorder is selected from the group consisting of tumors, neurological disorders, and brain injury or trauma. 
     
     
       17. The dosage formulation of  claim 1 , wherein the nanoparticles have an average diameter between about 60 and about 110 nm. 
     
     
       18. The dosage formulation of  claim 1 , wherein the nanoparticles have an average diameter of at least 110 nm and less than 200 nm. 
     
     
       19. The formulation of  claim 9 , wherein the therapeutic, prophylactic or diagnostic agent is loaded at a weight percent between about 1% and about 40% relative to the total weight of the nanoparticles and the therapeutic, prophylactic or diagnostic agent. 
     
     
       20. The formulation of  claim 9 , wherein the therapeutic, prophylactic or diagnostic agent is loaded at a weight percent between about 1% and about 10% relative to the total weight of the nanoparticles and the therapeutic, prophylactic or diagnostic agent.